Ranitidine structure

Starting with the archetypal H2 antagonist drugs cimetidine, tiotidine and ranitidine, structural modifications were made to reduce hydrogen-bonding abihty. These led to substantial improvements in brain penetration but still did not give the desired combination of brain penetrability and antagonist potency. 

The following amides prepared from 4-(3-nitro-l-pyrazolyl)butanoic acid, CDI, and primary amines represent partial structures of the histamine H2-receptor antagonists roxatidine, cimetidine, ranitidine, and famotidine [37]... 

The main clinical use of H2 receptor antagonists is to inhibit gastric secretion in the treatment of stomach ulcers. These agents all contain features that relate to the histamine structure, in particular the heterocyclic ring. Cimetidine and ranitidine are the most widely used in this class. 

Traditional or Hj antihistamine drugs block many effects caused by histamine however, it turns out that they are not able to withstand events mediated by H2 receptors, in particular excess gastric juice secretion. In 1977 an H2-receptor antagonist, cimetidine, was proposed, which revolutionized stomach ulcer treatment. Later on, ranitidine was proposed, followed by drugs with minor structural and pharmacological differences such as famotidine and nizatidine. 

Nizatidine Nizatidine is N-[2-[[[2-[(dimethylamino)methyl]-4-thiazolyl]methyl] thio] ethyl]-2-nitro-l,l-ethenediamine (16.2.15). According to its chemical structure, nizatidine is somewhat of a hybrid structure of ranitidine and famotidine, in which a side chain of ranitidine and carrying heterocycle, 2-aminothiazol, are used. Likewise, its synthesis also is a specific combination of pathways used for making both prototype drugs. 2-(Dimethyl-aminomethyl)-4-hydroxymethylthiazol serves as the initial compound, from which the desired nizatidine (16.2.15) is synthesized by subsequent reaction with 2-mercaptoethy-lamine hydrochloride and then with iV-methyl-l-methythio-2-nitroethenamine [71,72]. 

Taday, P.F. Bradley, I.V. Arnone, D.D. etal., Using terahertz pulse spectroscopy to study the crystalline structure of a drug A case study of the polymorphs of ranitidine hydrochloride /. Pharm. Sci. 2003, 92, 831-838. 

Attempts to quantitatively relate chemical structure to biological action were first initiated in the 19th century, but it was not until the 1960s that Hansch and Fujita devised a method that successfully incorporated quantitative measurements into SAR determinations (see section 4.4). The technique is referred to as QSAR (quantitative structure-activity relationships). One of its most successful uses has been in the development in the 1970s of the antiulcer agents cimetidine and ranitidine. Both SARs and QSARs are important parts of the foundations of medicinal chemistry. 

The discovery and development of cimetidine and ranitidine provided a revolution in the medical treatment and management of peptic ulcer disease. Subsequently, many pharmaceutical companies became involved in research programs to discover additional compounds as H2-receptor histamine antagonists. As a result, a very wide range of chemical structures now exists for this class of drug (for a review, see Cooper et al. [19]). Many of these compounds have been investigated in human studies, but only the above-mentioned five drugs - cimetidine, ranitidine, nizatidine, famotidine, and roxatidine - are marketed as medicines. 

When the FTIR spectra of polymorph systems differ substantially, the results may readily permit the identification of a particular form. For instance, the two forms of ranitidine hydrochloride yielded spectra that differed in the region above 3000 cm and in the regions spanning 2300-2700 cm and 1570-1620 cm b Zanoterone has been found to crystallize in a number of different forms, each of which yields a characteristic infrared spectrum. When solvent molecules are incorporated in a crystal lattice, the new structure is often sufficiently different from that of the anhydrous phase so that many of the molecular vibrational modes are altered. 

Cholerton, T.J. Hunt, J.H. Klinkert, G. Martin-Smith, M. Spectroscopic studies on ranitidine—its structure and the influence of temperature and pH. J. Chem. Soc. Perkin Trans. 2 1984, 1761-1766. 

Ranitidine has fewer side-effects than cimetidine, lasts longer, and is ten times more active. Structure-activity results for ranitidine include the following ... 

Comparison of the structures of histamine with cimetidine and ranitidine. The latter two are H2-receptor antagonists and act on the gastric parietal cells to inhibit gastric acid production. Ranitidine, which has a furan rather than an imidazole structure, is a more potent competitive inhibitor than cimetidine. 

Figure 2.3. Structural formulae of some Hrreceptor antagonists cimetidine (11). ranitidine (12). tiotidine (13) and L-643. 441 (14).

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